Chemoradiation improves survival for patients with locally advanced non-small cell lung cancer (NSCLC) over radiotherapy (R) alone. Les than 20% of patients have complete pathologic response to combination therapy. Paclitaxel (TXL) is effective as an anti-tumor agent and a radiosensitizer. Peripheral neurotoxicity and granulocytopenia limit its dosage; acute effects from TXL's infusion include nausea, hypotension, and cardiac arrhythmias related to Cremophor and ethanol. Conjugating TXL with poly-L-glutamate (PG-TXL/CT-2103) makes it water-soluble, allowing infusion of twice the amount of free TXL and higher intratumoral drug concentrations, which was confirmed by preclinical testing. Combining PG-TXL with radiation demonstrated synergistic radiation enhancement higher than that seen with other taxane or nucleoside analog. A phase I clinical trial of CT-2103 as single agent salvage therapy for patients with advanced solid tumors demonstrated safety and tolerability in dose up to 266 mg equivalent paclitaxel/m2 without significant alopecia. This Phase II STTR proposes a Phase I/II clinical trial of CT-213 given concurrently with chest RT in patients with unresectable Stage III or medically inoperable Stage II NSCLC. This study will determine MTD, DLT, pharmacokinetics, assess toxicity, and document patient costs. We expect this combination RT and CT-2103 to improve patient survival and response to treatment. PROPOSED COMMERCIAL APPLICATIONS: At M.D. Anderson Cancer Center, the combination of Taxol and cisplatin given concurrently with radiation therapy is the treatment of choice for lung cancer patients. In animal studies, CT-2103 is water soluble, infectable intravenously in 10 minutes without pre-medication, more effective (2-3X) and less toxic than Taxol. CT-2103 could possibly replace Taxol.